CADM1 isoforms differentially regulate human mast cell survival and homotypic adhesion

Area of Science:

• Immunology
• Cell Biology

Background:

• Cell Adhesion Molecule 1 (CADM1) mediates human lung mast cell (HLMC) adhesion to airway smooth muscle (ASM).
• The specific CADM1 isoforms expressed by HLMCs and their functional roles remain largely unknown.
• CADM1 influences HLMC proliferation and survival, contributing to ASM-dependent processes.

Purpose of the Study:

• To identify and characterize alternatively spliced CADM1 isoforms in human mast cells.
• To investigate the functional roles of different CADM1 isoforms in mast cell adhesion and survival.
• To elucidate the contribution of CADM1 isoforms to mast cell aggregation and viability.

Main Methods:

• Cloning of CADM1 isoforms from HLMCs and human mast cell lines (HMC-1, LAD2).
• Expression analysis of CADM1 isoforms in differentiated and immature mast cells.
• Functional assays assessing homotypic adhesion, cell viability, and protein expression following CADM1 manipulation (overexpression/downregulation).

Main Results:

• Three functional and one non-functional CADM1 isoforms were identified.
• Differentiated HLMCs and LAD2 cells predominantly expressed the SP4 isoform, alongside SP1 and a novel SP6 isoform.
• SP4 isoform overexpression enhanced mast cell homotypic adhesion more than SP1.
• CADM1 downregulation abolished homotypic adhesion, confirming CADM1 as the sole receptor for mast cell aggregation.
• SP4 overexpression promoted cell survival, while SP1 overexpression compromised it.
• CADM1 downregulation reduced viability, decreased Mcl-1(L) expression, and increased caspase-3/7 activity.

Conclusions:

• Human mast cells express multiple CADM1 isoforms with distinct functions in regulating survival and homotypic adhesion.
• The highly expressed SP4 CADM1 isoform is crucial for mast cell aggregation and longevity.
• CADM1 isoforms likely play significant roles in mastocytosis pathophysiology and allergic disease progression.