STING Gain-of-Function in Myeloid and Non-Hematopoietic Cells Compromises Lung Function 2309151

Abstract

Abstract Introduction Gain-of-function (GOF) mutations in the dsDNA sensing adaptor STING lead to a severe auto-inflammatory syndrome known as STING-Associated Vasculopathy with onset in Infancy (SAVI). Patients develop interstitial lung disease (ILD) resulting in respiratory failure. Mice heterozygous for the most common SAVI mutation, STING V154M/WT (VM), develop bronchus-associated lymphoid tissue (BALT) that is driven by VM-expressing endothelial cells (ECs). However, EC-specific VM expression is not sufficient for myeloid cell infiltration of lung tissue nor compromised lung function. Thus, we hypothesized that both non-hematopoietic cells (ECs) and VM-expressing myeloid cells are required to cause the lung disease phenotype exhibited by the original VM mice. Methods To better understand the role of hematopoietic cells in both BALT formation and lung dysfunction, we generated bone marrow radiation chimeras such that lethally irradiated WT or VM mice were reconstituted with bone marrow stem cells isolated from either WT mice or mice where VM expression was limited to myeloid cells. The VM mutation was restricted to myeloid cells by crossing VM conditional knock-in (CKI) mice to LysM-Cre mice (CKI x LysM-Cre). Results VM mice reconstituted with either WT or CKI x LysM-Cre stem cells developed extensive BALT formation. However, only the mice reconstituted with CKI x LysM-Cre stem cells exhibited significantly compromised lung function and this was associated with significantly increased myeloid cell infiltration of the lungs. WT mice reconstituted with CKI x LysM-Cre stem cells did not develop BALT, lung myeloid cell infiltration, or show compromised lung function. Conclusion STING GOF mutation in both myeloid and non-hematopoietic cells is required for compromised lung function that phenocopies the original VM mouse, highlighting a critical synergy between VM-expressing myeloid cells and VM-expressing non-hematopoietic cells in the development of fulminant lung disease. Funding Source R01HL165787, R21AI78978, T32A132152, 1F31HL180004-01 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)