Johns Hopkins Researchers Pinpoint How a Common Protein Triggers Chronic Inflammation and Raises CRP

One of the most frustrating puzzles in chronic disease research is why CRP, the standard blood marker of inflammation, stays persistently elevated in so many people even when there is no obvious infection or injury. The answer, it turns out, involves a set of interlocking molecular events that researchers have been piecing together for years. A new paper from Johns Hopkins University School of Medicine fills in a critical piece: the protein known as resistin appears to sit at the top of this chain, acting as both a primer and an activator of the NLRP3 inflammasome, one of the most consequential inflammatory switches in the human body. Understanding how this works matters for anyone trying to make sense of chronic inflammation, elevated CRP, and the conditions they accompany.

The research was covered in September 2026 by MedicalXpress and by Newswise as a Johns Hopkins press release, describing resistin as a "key driver of inflammation" and noting that blocking it could open new treatment pathways. The underlying paper, authored by Kariyawasam and colleagues from Johns Hopkins, was published in PLOS One in April 2026.

What Is the NLRP3 Inflammasome and Why Does It Matter?

The NLRP3 inflammasome is essentially the immune system's emergency alarm, and it is directly connected to the CRP your body produces. NLRP3 stands for NOD-, LRR-, and pyrin domain-containing protein 3. It forms a large protein scaffold inside macrophages, the immune cells that patrol tissues looking for threats. When the inflammasome assembles and activates, it acts like a switch that cleaves pro-caspase-1 into active caspase-1, which then processes the precursor proteins pro-IL-1 beta and pro-IL-18 into their mature, active forms. These cytokines are released into circulation, where they act on tissues throughout the body, including signaling the liver to produce acute-phase proteins.

C-reactive protein is one of the primary acute-phase proteins produced in response to IL-1 beta and the downstream signaling it provokes. IL-1 beta stimulates the release of interleukin-6 (IL-6), which in turn is the main signal that tells the liver to ramp up CRP synthesis. This chain, NLRP3 activation leading to IL-1 beta and IL-18 release, leading to IL-6 production, leading to elevated CRP, is now well established in the scientific literature. A comprehensive 2021 review in Circulation Research by Ridker and Rane described this pathway in detail and explained why targeting IL-6 has emerged as a strategy for reducing cardiovascular inflammation, with CRP serving as the downstream readout (pubmed.ncbi.nlm.nih.gov/33998272).

What has been less clear until recently is what reliably switches the NLRP3 inflammasome on in the context of chronic, metabolic inflammation. In acute illness, the triggers are easy to identify: bacterial toxins, cellular debris from damaged tissue, and crystals like uric acid (the driver of gout) are all well-documented NLRP3 activators. But explaining the persistent, low-grade NLRP3 activity seen in obesity, metabolic syndrome, type 2 diabetes, and atherosclerosis has required identifying a chronic trigger, one that is continuously elevated in these conditions. The new Johns Hopkins research points directly to resistin as that trigger.

What the New Research Found: Resistin as a Two-Stage Molecular Switch

Resistin is a small protein that circulates in the blood and is produced primarily by fat tissue and macrophages in humans. It was originally identified as a link between obesity and insulin resistance, but its inflammatory properties have attracted increasing scientific attention. Levels of resistin are elevated in people with obesity, metabolic syndrome, type 2 diabetes, rheumatoid arthritis, and cardiovascular disease, suggesting it may play a causal role in the inflammation common to these conditions rather than merely accompanying it.

The Johns Hopkins team found that human resistin (hResistin) activates the NLRP3 inflammasome through a two-stage process, and they mapped the molecular details of each stage. In the first stage, resistin causes macrophages to express and secrete a protein called HMGB1 (high mobility group box 1). HMGB1 then primes the inflammasome by driving the expression of NLRP3 itself, along with the precursor proteins pro-caspase-1, pro-IL-1 beta, and pro-IL-18. Think of this priming stage as loading the gun: the machinery for a large inflammatory response is being assembled and readied.

In the second stage, resistin directly binds to an enzyme called Bruton's tyrosine kinase (BTK), causing BTK to autophosphorylate and become active. Activated BTK then phosphorylates NLRP3 itself, which causes the inflammasome to assemble into its active form and fire. This second stage is what pulls the trigger: pro-caspase-1 is cleaved into active caspase-1, which then processes pro-IL-1 beta and pro-IL-18 into the mature cytokines that are secreted into circulation. The researchers confirmed this cascade using co-immunoprecipitation and western blot analyses, techniques that allow them to trace molecular interactions step by step.

The researchers also linked this pathway to a real disease endpoint, which gives the findings added clinical relevance. They studied pulmonary hypertension (PH), a serious condition involving abnormal blood vessel remodeling in the lungs. In mouse models of hypoxia-induced pulmonary hypertension, deleting the rodent equivalent of resistin (a protein called RELMalpha) reduced HMGB1, BTK, and NLRP3 levels in lung tissue. In lung tissue from actual patients with pulmonary hypertension, the colocalization of resistin, BTK, and NLRP3 in macrophages was substantially increased compared with healthy tissue. This confirms the pathway is active in human disease, not just in cell culture dishes.

Critically for the translational picture, the team found that blocking resistin with a human monoclonal antibody suppressed NLRP3 activation. This suggests the pathway is pharmacologically accessible: an antibody that neutralizes resistin could, in principle, prevent the priming and firing of the inflammasome without the broader immunosuppression that comes from blocking downstream cytokines. The researchers describe this as a "likely therapeutic pathway for NLRP3-driven inflammatory diseases," a category that includes not just pulmonary hypertension but cardiovascular disease, rheumatoid arthritis, gout, type 2 diabetes, and several neurological conditions.

Why This Matters for CRP and Chronic Inflammatory Conditions

The direct implication for CRP is straightforward: if resistin is a master switch for NLRP3, and NLRP3 drives the cytokine cascade that ultimately signals CRP production, then elevated resistin is a meaningful upstream contributor to elevated CRP. This helps explain a pattern that has puzzled clinicians for years. People with obesity, metabolic syndrome, or type 2 diabetes consistently show elevated CRP even in the absence of overt infection. Their CRP is not responding to a pathogen; it is responding to the sustained, low-grade activation of the NLRP3 inflammasome by chronically elevated resistin from expanded fat tissue and activated macrophages in that tissue.

The connection between resistin, metabolic status, and systemic inflammation had been noted in epidemiological studies, but the mechanistic link was missing. A 2026 review in the journal Cells by Nagasawa summarized how CRP now occupies a central position as a biomarker not just of acute illness but of the chronic inflammatory state underlying cardiovascular disease, diabetes, cancer, and neurological disorders, and called out the growing interest in new therapeutic strategies targeting the CRP-producing pathway (pubmed.ncbi.nlm.nih.gov/42274591). The resistin-NLRP3 paper provides one such upstream target.

Cardiovascular disease is perhaps the most clinically studied context for this pathway. A 2024 narrative review in Current Atherosclerosis Reports by Mehta, deGoma, and Shapiro summarized extensive evidence that higher IL-6 levels, driven in part by NLRP3-mediated IL-1 beta release, are independently associated with higher risk of cardiovascular death, heart attack, stroke, and peripheral artery disease, even after adjusting for traditional risk factors including high-sensitivity CRP itself (pubmed.ncbi.nlm.nih.gov/39589436). Understanding the upstream trigger of this cascade, which the resistin paper helps explain, moves the field closer to identifying people at risk earlier and potentially intervening further upstream in the disease process.

Existing and Emerging Approaches to the NLRP3 Pathway

The NLRP3 inflammasome is not a new therapeutic target, but resistin-specific inhibition would represent a novel entry point. The drug colchicine, a generic medication used for decades to treat gout and pericarditis, works in part by disrupting the machinery that assembles the NLRP3 inflammasome. A major clinical trial called COLCOT demonstrated in 2019 that colchicine reduced major cardiovascular events in patients after heart attack, an effect consistent with dampening inflammasome-driven inflammation. The LoDoCo2 trial extended that finding to stable coronary artery disease. These results helped establish NLRP3 as a clinically relevant cardiovascular target.

More specific NLRP3 inhibitors are now in clinical development. Several small molecule inhibitors that block NLRP3 directly are in phase 2 and phase 3 trials for conditions ranging from gout to heart failure. The appeal of targeting even further upstream, at the resistin-BTK-NLRP3 interface, is that it might suppress the chronic priming of the inflammasome in metabolic disease without the broader effects of direct NLRP3 blockade. It is still early research, and clinical trials testing resistin-targeting strategies would be needed to confirm whether this translates into measurable benefits for patients.

CRP as a Window Into Inflammasome Activity

From a practical standpoint, CRP remains the most accessible way to detect whether systemic inflammation, including NLRP3-driven inflammation, is elevated in an individual. Because IL-1 beta and IL-18 signal through IL-6 to drive CRP production in the liver, measuring CRP in the blood or, in consumer settings, in the saliva captures the cumulative output of multiple inflammatory pathways, including the NLRP3 cascade that resistin helps activate. High-sensitivity CRP, which can detect low-grade elevations in the 1 to 3 mg/L range, is particularly useful for tracking chronic background inflammation.

The value of tracking CRP over time is that it reflects the net effect of everything influencing your inflammatory state. Body fat percentage (which determines resistin output from adipose tissue), diet quality, sleep, physical activity, stress, and other factors all feed into the same downstream signal. Watching whether CRP trends upward or downward as you make lifestyle changes gives you a meaningful readout of whether those changes are affecting your inflammatory biology. Research like the resistin-NLRP3 paper enriches that readout by explaining some of the upstream biology. A CRP measurement is a general wellness indicator rather than a diagnosis of any specific condition, and anyone with persistently elevated levels should bring that data to a conversation with their healthcare provider.

What the Research Suggests for Lifestyle Choices

The resistin story adds molecular detail to what is already well established about metabolic health and inflammation: reducing adipose tissue, particularly visceral fat, lowers the output of inflammatory signals. Resistin is produced by fat cells and by macrophages that infiltrate fat tissue in large numbers as fat mass expands. Strategies that reduce fat mass, including a calorie-appropriate diet with adequate protein, regular physical activity, and sufficient sleep, also reduce resistin output and, in turn, the priming of NLRP3. Studies of dietary patterns consistently show that lower-fat mass is associated with lower CRP, and the resistin-NLRP3 pathway offers one mechanistic explanation for that association.

Dietary choices that reduce NLRP3 activation have received attention in the research literature as well. Omega-3 fatty acids, polyphenols found in berries and dark leafy greens, and the compounds in extra-virgin olive oil have all been shown to modulate the inflammatory signaling that feeds the NLRP3 pathway. The Mediterranean diet, which emphasizes these foods while limiting ultra-processed items and refined sugars, consistently produces reductions in CRP across clinical trials. These effects operate through multiple pathways, and while resistin is one upstream node, reducing the dietary triggers of NLRP3 directly, such as high saturated fat intake, adds another layer of modulation.

Chronic psychological stress and poor sleep are also relevant because they increase cortisol in ways that can promote macrophage activation and resistin release. Animal studies have shown that glucocorticoid signaling interacts with the NLRP3 pathway, and human epidemiological data consistently links poor sleep and high perceived stress to elevated CRP. Getting seven to nine hours of sleep per night and managing chronic stress through exercise, mindfulness, or social connection are interventions with robust support in the inflammation literature, and they are likely to operate in part through reducing the upstream triggers of NLRP3 activation, including resistin.

Sources

• Kariyawasam U, Lam W, Skinner J, et al. Human resistin is critical to activation of the NLRP3 inflammasome in macrophages. PLoS One, 2026; 21(4): e0337682. pubmed.ncbi.nlm.nih.gov/41961740
• Ridker PM, Rane M. Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease. Circulation Research, 2021; 128(11): 1728-1746. pubmed.ncbi.nlm.nih.gov/33998272
• Nagasawa M. CRP (C-Reactive Protein) Revisited: An Old Yet New Biomarker of Acute and Chronic Inflammation. Cells, 2026; 15(11). pubmed.ncbi.nlm.nih.gov/42274591
• Mehta NN, deGoma E, Shapiro MD. IL-6 and Cardiovascular Risk: A Narrative Review. Current Atherosclerosis Reports, 2024; 27(1): 12. pubmed.ncbi.nlm.nih.gov/39589436
• MedicalXpress. Study identifies key driver of inflammation, opening door to potential new treatments. September 2026. medicalxpress.com

Frequently Asked Questions

What is the NLRP3 inflammasome?

The NLRP3 inflammasome is a protein complex assembled inside immune cells, particularly macrophages, that acts as an internal alarm system. When activated, it cleaves precursor proteins into the pro-inflammatory cytokines IL-1 beta and IL-18, which then drive a broader inflammatory cascade that includes signaling the liver to produce C-reactive protein (CRP). NLRP3 activation has been linked to cardiovascular disease, type 2 diabetes, gout, rheumatoid arthritis, and several other chronic conditions.

What is resistin and how does it trigger inflammation?

Resistin is a small protein produced primarily by fat tissue and macrophages in humans. A 2026 study from Johns Hopkins University School of Medicine found that resistin activates the NLRP3 inflammasome through a two-stage process: first by causing macrophages to release HMGB1, which primes the inflammasome components, and second by binding to an enzyme called BTK, which then phosphorylates NLRP3 and triggers its assembly. This releases the inflammatory cytokines IL-1 beta and IL-18, which ultimately elevate CRP. Resistin levels are higher in people with obesity, metabolic syndrome, and type 2 diabetes, which helps explain the chronic low-grade inflammation common in those conditions.

Does elevated CRP reflect NLRP3 inflammasome activity?

Yes, indirectly. The NLRP3 inflammasome releases IL-1 beta, which stimulates the production of interleukin-6 (IL-6). IL-6 is the primary signal that tells the liver to synthesize CRP. So measuring CRP captures the downstream output of NLRP3 activation and the IL-1 beta/IL-6 signaling cascade it produces. High-sensitivity CRP can detect even low-grade inflammasome activity. Because CRP reflects many overlapping inflammatory pathways at once, it is a broad wellness indicator rather than a specific marker of any single pathway, and persistent elevations should be discussed with a healthcare provider.

What can I do to reduce resistin-driven inflammation?

Resistin is produced in fat tissue, so reducing excess adiposity through a balanced, calorie-appropriate diet and regular physical activity is the most direct lever. Specific foods that have been shown to modulate the NLRP3 pathway include omega-3 fatty acids found in oily fish, polyphenol-rich fruits and vegetables, and extra-virgin olive oil. Getting seven to nine hours of quality sleep per night and managing chronic psychological stress also reduce macrophage activation and inflammatory signaling. These lifestyle factors do not target resistin or NLRP3 specifically in the way a drug would, but they consistently lower CRP in clinical studies and are supported by robust evidence.