The dualistic role of Lyn tyrosine kinase in immune cell signaling: implications for systemic lupus erythematosus

Front Immunol. 2024 Jun 28:15:1395427. doi: 10.3389/fimmu.2024.1395427. eCollection 2024.

Abstract

Systemic lupus erythematosus (SLE, lupus) is a debilitating, multisystem autoimmune disease that can affect any organ in the body. The disease is characterized by circulating autoantibodies that accumulate in organs and tissues, which triggers an inflammatory response that can cause permanent damage leading to significant morbidity and mortality. Lyn, a member of the Src family of non-receptor protein tyrosine kinases, is highly implicated in SLE as remarkably both mice lacking Lyn or expressing a gain-of-function mutation in Lyn develop spontaneous lupus-like disease due to altered signaling in B lymphocytes and myeloid cells, suggesting its expression or activation state plays a critical role in maintaining tolerance. The past 30 years of research has begun to elucidate the role of Lyn in a duplicitous signaling network of activating and inhibitory immunoreceptors and related targets, including interactions with the interferon regulatory factor family in the toll-like receptor pathway. Gain-of-function mutations in Lyn have now been identified in human cases and like mouse models, cause severe systemic autoinflammation. Studies of Lyn in SLE patients have presented mixed findings, which may reflect the heterogeneity of disease processes in SLE, with impairment or enhancement in Lyn function affecting subsets of SLE patients that may be a means of stratification. In this review, we present an overview of the phosphorylation and protein-binding targets of Lyn in B lymphocytes and myeloid cells, highlighting the structural domains of the protein that are involved in its function, and provide an update on studies of Lyn in SLE patients.

Keywords: Lyn tyrosine kinase; SLE; Src family kinases; autoimmune disease; autoinflammation; immunoreceptor signaling; inhibitory signaling; lupus.

Publication types

  • Review

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Humans
  • Lupus Erythematosus, Systemic* / genetics
  • Lupus Erythematosus, Systemic* / immunology
  • Mice
  • Signal Transduction*
  • src-Family Kinases* / genetics
  • src-Family Kinases* / metabolism

Substances

  • src-Family Kinases
  • lyn protein-tyrosine kinase

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grant funding from the Lupus Research Alliance (to MLH) and the School of Translational Medicine, Monash University (to MW and MH). EL’E-S was supported by an Australian Government Research Training Program (RTP) Scholarship administered by Monash University.