Monocyte PTGS2 Emerges as a Driver of Infliximab Non-Response in Ulcerative Colitis
Primary non-response to infliximab remains one of the most frustrating gaps in ulcerative colitis care. Patients can enter induction therapy with reasonable expectations and still fail to achieve meaningful clinical or endoscopic improvement, leaving clinicians with limited time to adjust treatment and little clarity on why the biologic never gained traction. This study points to a specific inflammatory circuit in the colon: excessive neutrophil infiltration, driven in part by PTGS2 expression in inflammatory monocytes.
The work begins with human colonic RNA-sequencing data and then moves across multiple layers of validation, including clinical samples, virtual gene knockout analysis, single-cell RNA sequencing, cell-based experiments, and a DSS-induced murine colitis model. In the retrospective patient cohort, 44 people with moderate-to-severe ulcerative colitis received infliximab as first biologic therapy. At week 14, 23 met the response definition and 21 did not. Response was defined by improvement in the Modified Mayo Disease Activity Index together with endoscopic improvement, giving the investigators a clinically grounded way to separate primary responders from primary non-responders.
What distinguished the non-response state was not simply generalized inflammation, but a neutrophil-heavy colonic immune profile before treatment began. That pattern matters because neutrophils are not passive bystanders in ulcerative colitis; they can amplify tissue injury, sustain mucosal inflammation, and make a TNF-α blocker look weaker than it should in a more permissive inflammatory environment. The dataset linked this pattern to PTGS2, which correlated positively with neutrophil infiltration and appeared predominantly in colonic CD14+S100A9+ inflammatory monocytes.
PTGS2 Sits Upstream of a Neutrophil-Recruiting Inflammatory Loop
The mechanistic signal in this paper is straightforward and biologically plausible. PTGS2, also known as cyclooxygenase-2, is embedded in inflammatory signaling pathways that can shape chemokine production, leukocyte trafficking, and mucosal injury. Virtual knockout of PTGS2 shifted genes tied to neutrophil chemotaxis, with enrichment in the NF-κB axis, a pathway long associated with intestinal inflammation and myeloid activation.
A single sentence captures the clinical implication: infliximab may be entering an inflammatory microenvironment already primed to recruit neutrophils aggressively.
Single-cell profiling sharpened the cellular source. The dominant PTGS2 signal came from inflammatory monocytes rather than from a diffuse, nonspecific immune background. That detail is important because it narrows the therapeutic target from a broad anti-inflammatory concept to a defined myeloid population that may be setting the pace for downstream chemokine release, especially CXCL8-mediated recruitment of neutrophils.
The authors then connected that biology to an intervention candidate: Gegen Qinlian Decoction (GQD), a traditional Chinese herbal formula. Network pharmacology and molecular docking suggested that GQD could engage PTGS2 through multiple bioactive constituents, with quercetin showing the strongest binding affinity among the tested compounds. The point here is not that a single herb acts like a conventional biologic, but that a multi-component formula may converge on the inflammatory circuitry implicated in non-response.
Quercetin Dampened PTGS2-Dependent Chemotaxis in Monocyte Models
In THP-1 cells, quercetin suppressed LPS-induced PTGS2 expression and reduced the downstream NF-κB/CXCL8 signaling associated with neutrophil chemotaxis. The investigators did not stop at a correlation between compound and gene expression. They used PTGS2 knockdown and overexpression experiments to test whether the pathway could be moved in either direction. Those experiments supported PTGS2 as a functional node rather than a bystander marker.
This cell work matters because it links a molecular observation to a tractable mechanism: if inflammatory monocytes overexpress PTGS2, they may generate a chemotactic field that attracts neutrophils into the colon, deepening mucosal injury and blunting the apparent effect of TNF blockade. Quercetin’s effect was framed as suppression of that loop, not as a broad and nonspecific immunosuppressive response.
The mouse experiments moved the hypothesis closer to therapy, though still within a preclinical model. In DSS-induced colitis, GQD reduced PTGS2 expression and neutrophil accumulation in the inflamed colon. It also improved disease severity and enhanced the response to anti-TNF-α treatment used in the murine system as a surrogate for infliximab, since human infliximab does not neutralize murine TNF-α in vivo.
Adjunctive Therapy May Matter Most When Anti-TNF Alone Falls Short
The treatment design is clinically intuitive. Anti-TNF monotherapy at the chosen mouse dose was intentionally set to produce limited efficacy, creating a model in which an adjunct could be judged against a weak baseline response. GQD then functioned as a potentiator of anti-TNF activity rather than as a standalone replacement. In practical terms, the study argues that some cases of primary non-response may reflect an inflammatory architecture that needs to be altered before TNF blockade can work well.
A second sentence is worth stating plainly: the proposed target is not TNF itself, but the myeloid machinery that helps sustain a neutrophil-rich colon.
The strengths of the study lie in its layered approach. Human tissue data, immune infiltration analysis, single-cell transcriptomics, and experimental validation all pointed toward the same axis. The weaknesses are equally clear. The clinical cohort was retrospective and relatively small, the patient analysis did not establish causality, and the therapeutic findings remain preclinical. The herbal formula also contains multiple constituents, so isolating the contribution of any single component beyond quercetin will require additional work.
Even so, the clinical message is concrete. Primary infliximab non-response in ulcerative colitis may not simply reflect inadequate TNF blockade; it may reflect an inflammatory circuit dominated by monocyte-derived PTGS2 and neutrophil recruitment. If that biology holds in larger human studies, it could help identify patients less likely to benefit from infliximab alone and open the door to combination strategies aimed at the myeloid compartment rather than at TNF signaling alone. For now, the strongest claim is narrower: PTGS2 deserves attention as a candidate biomarker and therapeutic target in patients whose colon remains neutrophil-rich before infliximab ever has a chance to work.