Participation of the NOD2/RIPK2 signaling pathway in the pathophysiology of psoriasis.

• Grant number: 24/20897-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2025
• End date: January 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: José Carlos Farias Alves Filho
• Grantee: Micaely Lorrana Pereira Conceição
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Psoriasis is a systemic inflammatory disease, primarily affecting the skin. It is characterized by hyperactivation and high proliferation of keratinocytes, along with an increased infiltration of inflammatory cells in the skin. Despite recent advancements in understanding the pathophysiology and treatment of the disease, the mechanisms of disease development and chronicity remain poorly understood. To identify new targets potentially involved in psoriasis pathophysiology, we conducted an in silico analysis of public transcriptomic data from the skin of psoriasis patients, comparing lesional and non-lesional skin. We identified the NOD-like receptor signaling pathway as one of the main differentially expressed pathways. Supporting these findings, we also observed a differential relative expression of NOD2 and RIPK2 in lesional and non-lesional skin of psoriasis patients. These findings align with previous studies showing that NOD receptor signaling is increased in the skin of psoriasis patients, including the NOD2 gene. Previous data from our group demonstrate that total genetic absence of Ripk2 exacerbates skin inflammation in an imiquimod (IMQ)-induced preclinical psoriasis model, assessed by skin thickness, histological sections, and bioluminescence assays. Interestingly, through scRNAseq analyses of public datasets from preclinical and clinical psoriasis models, we identified RIPK2 expression predominantly in dendritic cells (DCs). Complementing these data, bone marrow-derived dendritic cells (BMDCs) from Ripk2-deficient mice exhibit a higher activation profile, with increased production of IL-6, TNF-a, and activation molecules such as CD80 and CD86, compared to BMDCs from WT mice. Taken together, our findings so far demonstrate that the genetic absence of Ripk2 engages an activation program in dendritic cells in vitro and exacerbates psoriasiform inflammation by enhancing the cutaneous IL-23/IL-17a axis. However, the mechanisms by which RIPK2 regulates this axis remain poorly understood. Therefore, our goal is to investigate the immunoregulatory mechanisms of the NOD2/RIPK2 pathway in psoriasis pathogenesis.