Blnk, also known as B cell linker protein, is crucial for orchestrating B cell receptor-associated spleen tyrosine kinase (Syk) signaling [1,2,5]. It connects Syk and Btk to calcium signals, and mediates Syk-dependent Btk activation, which is essential in B cell antigen receptor (BCR)-coupled signaling [2,5]. Blnk is also involved in the pre-B cell receptor signaling cascade, playing a key role in human B-cell differentiation [6].

In macrophage-related studies, Blnk negatively regulates innate antifungal immunity. Fungal β-glucans or α-mannans stimulation leads to CLRs governing Syk-mediated activation of Blnk, which disrupts podosome ring formation and impedes macrophage migration. Mechanistically, Blnk associates with casitas B-lineage lymphoma (c-Cbl), interfering with c-Cbl and Src-family kinase Fyn interaction, thus disrupting Fyn-mediated phosphorylation of c-Cbl and c-Cbl-associated F-actin assembly. Mice with monocyte-specific Blnk deficiency show heightened resistance to Candida albicans infection due to increased infiltration of Ly6C+ macrophages into renal tissue [1]. In chondrocytes, silencing Blnk protects against interleukin-1β-induced chondrocyte injury through the NF-κB signaling pathway, and delays osteoarthritis (OA) progression [3]. In BCR-ABL1-transformed pro-B cells, Blnk reduces Bcr-Abl kinase activity to induce cell cycle arrest and decrease genomic instability, and suppresses the PI3K/Akt pathway [4].

In conclusion, Blnk is a key regulator in B-cell development and signaling, as well as in macrophage-mediated innate antifungal immunity and chondrocyte injury-related OA progression. Gene knockout mouse models have been instrumental in revealing Blnk's functions in these biological processes and disease conditions, providing valuable insights into its roles in B-cell immunodeficiencies, fungal infections, and OA [1,3,4,6].