A Novel Mechanism in Psoriatic Disease Pathogenesis

By M. Elaine Husni, MD, MPH, and Unnikrishnan M. Chandrasekharan, PhD

One of the major focuses of the Husni laboratory is uncovering signaling pathways that drive the progression of psoriatic diseases, focusing specifically on tumor necrosis factor-alpha (TNF-α) receptor signaling. At the beginning of this discovery, we demonstrated that the depletion of TNF receptor 2 (TNFR2), but not TNFR1, significantly reduces psoriasis-like inflammation in a murine model with TNFR knockout (KO) mice. Importantly, this reduction in disease severity correlates with a diminished dendritic cell (DC) population in secondary lymphoid organs, such as the spleen and lymph nodes. This pivotal finding highlights the previously unrecognized role of the TNFR2/DC axis in psoriatic diseases.

Dendritic cells

TNFR2 promotes PsA-like inflammation potentially through cDC1 activation. Dendritic cells are a heterogeneous subset of antigen-presenting cells linking the innate and adaptive arms of the immune system. DCs have been implicated in numerous inflammatory and autoimmune diseases, including psoriatic arthritis (PsA).

Our current research investigates the role of DC-specific TNFR2 (DC-TNFR2) in PsA. Our results suggest that TNFR2 facilitates PsA-like inflammation by activating conventional dendritic cell type 1 (cDC1), a key subset of antigen-presenting cells. Activated DCs produce pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-12 and IL-23, driving the differentiation of naive T cells into Th1 and Th17 subtypes — critical mediators of psoriatic diseases.

To investigate the role of DC-TNFR2 in PsA, we utilized a mannan oligosaccharide (MOS)-induced model of PsA in DC-TNFR2KO mice. These models, generated by crossing TNFR2-floxed (TNFR2 fl/fl) with CD11c-Cre models, exhibit TNFR2 deletion specifically in DCs. In TNFR2-intact control models, MOS treatment induced pronounced scaling, redness and thickness of the skin, along with joint inflammation. Remarkably, these symptoms were significantly attenuated in DCTNFR2KO models, as evidenced by reduced cumulative Psoriasis Area and Severity Index (PASI) scores and lower arthritis severity scores on days four and six after MOS treatment. Moreover, MOS-induced redness, swelling and inflammation in the paws were attenuated in the DC-TNFR2KO models. Similarly, the mean arthritis severity score significantly decreased in DCTNFR2KO models on day four and day six.

There are three major DC subsets: plasmacytoid DC (pDC), cDC1 and conventional DC2 (cDC2). MOS-induced PsA increased the cDC1 populations in the spleen of the controls, but not in DC-TNFR2KO models. Conversely, the cDC2 population did not change significantly, underscoring the specificity of the TNFR2-cDC1 axis in PsA pathogenesis.

Potential therapeutic avenues

Our findings establish the TNFR2/cDC1 axis as a previously uncharacterized mechanism driving PsA. This discovery opens exciting avenues for therapeutic innovation. Selectively targeting TNFR2-dependent cDC1 activation pathways may offer a more precise and safer alternative to global anti-TNF agents, which inhibit both TNFR2 and TNFR1, often leading to adverse effects.

By focusing on this pathway, future treatments could potentially attenuate PsA pathogenesis while preserving essential immune functions, thus revolutionizing the management of psoriatic diseases. These findings illuminate a transformative path in our understanding of PsA, offering hope for novel and highly targeted interventions that could improve patient outcomes and quality of life.

Lab members Raminderjit Kaur, PhD; Vincent Del Signore, BS; Jean Lin, MD; and Shashank Cheemalavagu, MD, contributed to this research.