Clinical and Hematologic Effects of Endotoxin in Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome Model Mice.
Shamik MajumdarJi-Liang GaoSergio M PontejoKarl BalabanianFrançoise BacheleriePhilip M MurphyPublished in: ImmunoHorizons (2022)
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome immunodeficiency is caused by autosomal dominant gain-of-function CXCR4 mutations that promote severe panleukopenia caused by bone marrow retention of mature leukocytes. Consequently, WHIM patients develop recurrent bacterial infections; however, sepsis is uncommon. To study this clinical dichotomy, we challenged WHIM model mice with LPS. The LD 50 was similar in WHIM and wild-type (WT) mice, and LPS induced acute lymphopenia in WT mice that was Cxcr4 independent. In contrast, in WHIM mice, LPS did not affect circulating T cell levels, but the B cell levels anomalously increased because of selective, cell-intrinsic, and Cxcr4 WHIM allele- dependent emergence of Cxcr4 high late pre-B cells, a pattern that was phenocopied by Escherichia coli infection. In both WT and WHIM mice, the CXCR4 antagonist AMD3100 rapidly increased circulating lymphocyte levels that then rapidly contracted after subsequent LPS treatment. Thus, LPS-induced lymphopenia is CXCR4 independent, and a WHIM mutation does not increase clinical LPS sensitivity. Anomalous WT Cxcr4 -independent, but Cxcr4 WHIM-dependent, promobilizing effects of LPS on late pre-B cell mobilization reveal a distinct signaling pathway for the variant receptor.
Keyphrases
- inflammatory response
- wild type
- high fat diet induced
- lps induced
- escherichia coli
- cell migration
- bone marrow
- anti inflammatory
- signaling pathway
- type diabetes
- magnetic resonance
- adipose tissue
- end stage renal disease
- magnetic resonance imaging
- single cell
- insulin resistance
- epithelial mesenchymal transition
- gene expression
- ejection fraction
- case report
- pseudomonas aeruginosa
- acute kidney injury
- peritoneal dialysis
- pi k akt
- multidrug resistant
- binding protein