A stress sensor, IRE1α, is required for bacterial-exotoxin-induced interleukin-1ß production in tissue-resident macrophages.

Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1ß (IL-1ß), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarify the roles of inositol-requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1ß production in RPMs. In RPMs, CTB is incorporated into the ER and induces ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α-deficient RPMs show a significant impairment of CT- or CTB-induced IL-1ß production, indicating that IRE1α is required for CT- or CTB-induced IL-1ß production in RPMs. This study demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages.

Autosomal Dominant Hypocalcemia With Atypical Urine Findings Accompanied by Novel CaSR Gene Mutation and VitD Deficiency.

INTRODUCTION: Autosomal dominant hypocalcemia (ADH) is caused by gain-of-function mutations of the calcium sensing receptor (CaSR). It is characterized by hypercalciuria in spite of hypocalcemia. Vitamin D deficiency increases calcium reabsorption in the distal tubules of the kidneys, resulting in hypocalciuria. MATERIALS AND METHODS: A 38-year-old female proband had hypocalcemia, hypocalciuria, and vitamin D deficiency. Her father and brother also had hypocalcemia, but her mother was normocalcemic. We analyzed the CaSR gene abnormality in this family. Polymerase chain reaction (PCR) and sequence analysis were performed to explore the CaSR gene mutation. Mutagenesis, transfection, and functional analysis were performed on the discovered genetic abnormalities. RESULT: PCR and sequence analysis revealed that the proband, her father, and brother had a novel heterozygous mutation of the CaSR genes that causes threonine to asparagine substitution at codon 186 (T186N). Using HEK293 cells transfected with wild-type or T186N CaSR complementary DNA, we assessed the intracellular Ca2+ concentration in response to changes in the extracellular Ca2+ concentration. The cells transfected mutant CaSR gene had higher activity than that of wild-type. Therefore, we determined our patient had ADH with a novel mutation of the CaSR gene and hypocalciuria resulting from a vitamin D deficiency. We administered vitamin D to the proband, which caused elevation of her urinary calcium level, a typical finding of ADH. CONCLUSION: Vitamin D deficiency was suggested to potentially mask hypercalciuria in ADH. Hypocalcemia with vitamin D deficiency should be diagnosed with care.