PuSH - Publication Server of Helmholtz Zentrum München: A20 and the non-canonical NF-κB pathway are key regulators of neutrophil recruitment during fetal ontogeny.

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Rohwedder, I.* ; Wackerbarth, L.M.* ; Heinig, K.* ; Ballweg, A.* ; Altstätter, J.* ; Ripphahn, M.* ; Nussbaum, C.* ; Salvermoser, M.* ; Bierschenk, S.* ; Straub, T.* ; Gunzer, M.* ; Schmidt-Supprian, M.* ; Kolben, T.* ; Schulz, C.* ; Ma, A.* ; Walzog, B.* ; Heinig, M. ; Sperandio, M.*

A20 and the non-canonical NF-κB pathway are key regulators of neutrophil recruitment during fetal ontogeny.

JCI insight 8:e155968 (2023)

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Newborns are at high risk of developing neonatal sepsis, particularly if born prematurely. This has been linked to divergent requirements the immune system has to fulfill during intrauterine compared to extrauterine life. By transcriptomic analysis of fetal and adult neutrophils we set out to shed new light on the molecular mechanisms of neutrophil maturation and functional adaption during fetal ontogeny. We identified an accumulation of differentially regulated genes within the non-canonical NF-κB signaling pathway accompanied by constitutive nuclear localization of RelB and increased surface expression of TNFRII in fetal neutrophils as well as elevated levels of LT-α in fetal serum. Furthermore, we found strong upregulation of the negative inflammatory regulator A20 (Tnfaip3) in fetal neutrophils, which was accompanied by a pronounced downregulation of the canonical NF-κB pathway. Functionally, overexpressing A20 in Hoxb8 cells led to reduced adhesion of these neutrophil-like cells under flow. Conversely, mice with a neutrophil specific A20 deletion displayed increased inflammation in vivo. Taken together, we have uncovered constitutive activation of the non-canonical NF-κB pathway with concomitant upregulation of A20 in fetal neutrophils. This offers perfect adaption of neutrophil function during intrauterine fetal life, but also restricts appropriate immune responses particularly in prematurely born infants.

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