Joosten, L. A. | Search bioRxiv

bioRxiv2020

The impact of rare and common genetic variation in theInterleukin-1 pathway for human cytokine responses

BackgroundInterleukin(IL)-1 signaling is of major importance in human innate cytokine responses. Common variants in related genes have been linked to various inflammation-mediated diseases and stimulation-induced cytokine responses, but the role of rare variants remains to be elucidated. MethodsIn this study, we characterize the role of rare and common genetic variation, as identified by molecular inversion probe-based sequencing, in 48 genes related to the IL-1 pathway. Using a systems biology approach, we examined the inter-individual variability of in vitro stimulation-specific human cytokine responses from 463 healthy individuals of the Human Functional Genomics Project and assessed the role of rare and common genetic variants, separately and combined, by means of the Sequence Kernel Association Test. ResultsWe identified strong associations for rare genetic variants in NCF4 (adjP=7.2E-05) and CASP1 (adjP=3.0E-05) with IL-6 production in response to PHA and LPS stimulation, respectively. In addition, common variants in IL36A and IL38 were associated to both C. albicans-induced IL-1{beta} (IL36A adjP=0.0442; IL38 adjP=0.0092) and IL-6 production (IL36A adjP=0.0037; IL38 adjP=0.0082), an effect that was stronger at the subpathway level both for IL-1{beta} (adjP=0.0017) and IL-6 (adjP=1.8E-04). The common variant signature for the IL-1{beta} and IL-6 response to C. albicans was confirmed by an association with all anti-inflammatory genes (adjP=1.87E-03 and adjP=5.75E-04), and we validated this finding for non-coding common variants. Lastly, we identified a burden of rare variants in pro-inflammatory genes and LPS-induced IL-6 production (adjP=2.42E-04), and a new role for anti-inflammatory rare variants on S. aureus-stimulated IL-6 production (adjP=6.71E-03). ConclusionsIn conclusion, we show that both common and rare genetic variation in genes of the IL-1 pathway, separately and combined, differentially influence in vitro cytokine responses to various stimuli in healthy individuals. This study therefore accentuates potential mechanisms that are translatable into new hypothesis-driven characterization of common and rare variant involvement in a wide variety of inflammatory and immunological mechanisms and diseases.

systems biology↗

bioRxiv2019

Heme induces innate immunity memory

Trained immunity defines long-lasting adaptive responses of innate immunity, mediated by transcriptional and epigenetic modifications of myeloid cells. Here, we report that labile heme, an alarmin released extracellularily upon tissue damage and hemolysis, induces trained immunity in human and murine primary cells and in mice. Heme-trainning in monocytes is associated with epigenetic and transcriptional profiles that overlap to some extent with those seen in {beta}-glucan-training, the prototype agonist of trained immunity. In sharp contrast to {beta}-glucan training however, heme-training relied on activation of the Syk/JNK-pathway. Heme training in mice was associated with long-lasting expansion of myeloid-biased progenitor cells as well as with altered chromatin accessibility in hematopoietic stem and progenitor cells. Finally, heme-induced training was protective against bacterial sepsis in mice. In conclusion, we reveal that heme, a bona fide alarmin, induces innate immune memory regulating host response to infection.

immunology↗