Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model

Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-gamma), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-gamma signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Fas(lpr)/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8(+) and CD4(+) T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naive T lymphocyte ratio for both CD4(+) and CD8(+) cells, and reduced the frequency of GL7(+) germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

Automated summary

Autoimmune diseases are largely caused by activated lymphocytes producing a pathogenic cytokine environment. One approach to treating autoimmune diseases involves targeting the SOCS1 pathway with a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR). This treatment has shown promise in reducing auto-reactive lymphocyte effector functions and mitigating autoimmune pathologies.