2 research outputs found
ILâ1β prevents ILC2 expansion, type 2 cytokine secretion, and mucus metaplasia in response to earlyâlife rhinovirus infection in mice
BackgroundEarlyâlife wheezingâassociated respiratory infection with human rhinovirus (RV) is associated with asthma development. RV infection of 6âdayâold immature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with the expansion of ILâ13âproducing type 2 innate lymphoid cells (ILC2s) and dependent on ILâ25 and ILâ33. We examined regulation of this asthmaâlike phenotype by ILâ1β.MethodsSixâdayâold wildâtype or NRLP3â/â mice were inoculated with sham or RVâA1B. Selected mice were treated with ILâ1 receptor antagonist (ILâ1RA), antiâILâ1β, or recombinant ILâ1β.ResultsRhinovirus infection induced Il25, Il33, Il4, Il5, Il13, muc5ac, and gob5 mRNA expression, ILC2 expansion, mucus metaplasia, and airway hyperresponsiveness. RV also induced lung mRNA and protein expression of proâILâ1β and NLRP3 as well as cleavage of caspaseâ1 and proâILâ1β, indicating inflammasome priming and activation. Lung macrophages were a major source of ILâ1β. Inhibition of ILâ1β signaling with ILâ1RA, antiâILâ1β, or NLRP3 KO increased RVâinduced type 2 cytokine immune responses, ILC2 number, and mucus metaplasia, while decreasing ILâ17 mRNA expression. Treatment with ILâ1β had the opposite effect, decreasing ILâ25, ILâ33, and mucous metaplasia while increasing ILâ17 expression. ILâ1β and ILâ17 each suppressed Il25, Il33, and muc5ac mRNA expression in cultured airway epithelial cells. Finally, RVâinfected 6âdayâold mice showed reduced ILâ1β mRNA and protein expression compared to mature mice.ConclusionMacrophage ILâ1β limits type 2 inflammation and mucous metaplasia following RV infection by suppressing epithelial cell innate cytokine expression. Reduced ILâ1β production in immature animals provides a mechanism permitting asthma development after earlyâlife viral infection.Earlyâlife rhinovirus infection increases epithelial expression of the innate cytokines ILâ25 and ILâ33, expands (type 2 innate lymphoid cells) ILC2s, and enhances development of an asthmaâlike phenotype. Rhinovirus causes macrophage (NLR family, pyrin domain containing 3) NLRP3 inflammasome activation and bioactive ILâ1β production. ILâ1β production, which is deficient in immature mice, attenuates production of ILâ25 and ILâ33, thereby protecting against rhinovirusâinduced asthma development.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156197/3/all14241_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156197/2/all14241.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156197/1/all14241-sup-0001-FigS1.pd
Inflammatory Biomarker Profiles in Very Preterm Infants within the Context of Preeclampsia, Chorioamnionitis, and Clinically Diagnosed Postnatal Infection
Preterm delivery can be precipitated by preeclampsia or infection, and preterm infants are at heightened risk of postnatal infection. Little is known about the ontogeny of inflammatory biomarkers in extremely preterm infants. We hypothesized that suspected prenatal infection (clinical chorioamnionitis or spontaneous preterm labor) and clinically diagnosed postnatal infection would be associated with unique biomarker signatures, and those patterns would be influenced by the degree of prematurity. Venous blood was collected daily for the first week and weekly for up to 14 additional weeks from 142 neonates born at 22â32 weeks gestation. A custom array was utilized to measure monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). C-reactive protein (CRP) levels were obtained from the electronic medical record. Independent of gestational age, MCP-1 was significantly increased (p p p < 0.01) in the presence of chorioamnionitis with funisitis. IL-6 and CRP were both increased in infants diagnosed with postnatal infection, with peak levels observed on days 2 and 3, respectively. In conclusion, suspected prenatal and postnatal infections and non-infectious complications of pregnancy are associated with unique biomarker profiles, independent of gestational age, including over a 2-fold increase in MCP-1 among newborns of mothers with preeclampsia. Further, in those clinically diagnosed with a postnatal infection in the absence of antenatal infection concerns, IL-6 increases before CRP, emphasizing a potential role for expanded biomarker screening if antibiotics are initially avoided in infants delivered for maternal indications