Type I Interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression via activation of p38 MAPK

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Interferons (IFNs) are key regulators of a number of inflammatory conditions in which neutrophils play an important role in pathology, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), where Type I IFNs are implicated in disease pathology. However, IFNs are usually generated <jats:italic>in vivo</jats:italic> together with other cytokines that also have immunoregulatory functions but such interactions are poorly-defined experimentally. We measured the effects of Type-I IFN (IFN<jats:italic>α</jats:italic>), elevated in both RA and SLE, on the functions of healthy neutrophils incubated <jats:italic>in vitro</jats:italic> in the absence and presence of pro-inflammatory cytokines typically elevated in inflammatory diseases (TNF<jats:italic>α</jats:italic>, GM-CSF). IFN<jats:italic>α</jats:italic> alone had no effect on neutrophil apoptosis, however it did abrogate the anti-apoptotic effect of GM-CSF (18h, p&lt; 0.01). The enhanced stabilty of the anti-apoptotic protein Mcl-1 and delayed activation of caspase activation normally regulated by GM-CSF were blocked by IFN<jats:italic>α</jats:italic>: this effect was mediated, in part, by activation of p38 MAPK, increased turnover of the anti-apoptotic protein Mcl-1 and cleavage of caspases. IFN<jats:italic>α</jats:italic> alone also primed ROS production alone and maintained the transient priming effect of TNF for up to 4h: it also down-regulated GM-CSF and TNF<jats:italic>α</jats:italic>-activated expression of CXCL1, CXCL2, CXCL3, CXCL8, CCL3 and CCL4, but in contrast increased the expression of CXCL10. These novel data identify complex regulatory signalling networks in which Type I IFNs profoundly alter the response of neutrophils to inflammatory cytokines. This is likely to have important consequences <jats:italic>in vivo</jats:italic> and may explain the complexity and heterogeneity of inflammatory diseases such as RA, in which multiple cytokine cascades have been activated.</jats:p>

Intratumoral pro-oxidants promote cancer immunotherapy by recruiting and reprogramming neutrophils to eliminate tumors

“…NOX organizer or NOXO1) subunits of NOX, as measured by their mRNA levels [ 81 ]. IFNα alone also primes neutrophil ROS production and maintains the transient priming effect of TNFα for several hours: It also down-regulates GM-CSF- and TNFα-activated expression of chemokine (C-X-C motif) factors, CXCL1, CXCL2, CXCL3, CXCL8, CCL3 and CCL4 characteristic of N2 neutrophils [ 83 ]. However, by contrast, IFNα also increases the expression of CXCL10 (a.k.a.…”

“…However, by contrast, IFNα also increases the expression of CXCL10 (a.k.a. IP-10) [ 83 ], a marker of N1 neutrophils. Hence, the balance between various levels of cytokines and chemokines in tumors will dictate the subtype of neutrophils they contain.…”