The Role Of Alarmins, Invariant Nkt Cells And Senescence In The Pathophysiology Of Sterile Intra-Amniotic Inflammation

Preterm birth is defined as the delivery of a live baby prior to the 37th week of gestation. It is the leading cause of neonatal mortality worldwide. Preterm neonates are at a higher risk for short- and long-term complications, and prematurity places significant burden on our society. Elucidation of the mechanisms that lead to spontaneous preterm labor will enable development of therapies to prevent this syndrome. We aimed to study pathological inflammation that is implicated in the pathophysiology of spontaneous preterm labor. Pathological inflammation can be initiated by the activation of innate immunity either by microorganisms or alarmins, which are endogenous danger signals derived cellular stress or injury. The inflammatory process initiated by alarmins in the amniotic cavity is referred to as sterile intraamniotic inflammation because it occurs in the absence of detectable microbial infection. Sterile intra-amniotic inflammation is more common than microbial-associated intra-amniotic inflammation in patients with intact chorioamniotic membranes who undergo spontaneous preterm labor, and administration of such alarmins as IL1α or HMGB1 was shown to induce preterm birth. Our major aim was to determine whether HMGB1 and three additional alarmins (S100A12, monosodium urate, and HSP70) are capable of inducing sterile inflammation of the chorioamniotic membranes and by what molecular mechanism. Our findings show that HMGB1, S100A12, monosodium urate, and HSP70 greatly increase secretion of pro-inflammatory cytokine IL-1β from the chorioamniotic membranes and up-regulate other pro-inflammatory pathways leading to collagen remodeling and synthesis of labor promoting enzyme prostaglandin synthase 2. We also found that activation of iNKT cells, which was shown to occur via stimulation with alarmins, induces preterm birth in mice by activating CD4+ and CD8+ T cells as well as innate immune cells and by establishing pro-inflammatory microenvironment at the maternal-fetal interface. We also identified rosiglitazone, an anti-inflammatory drug that dampens iNKT-dependent inflammation, as a potent treatment for preterm labor in mice. Finally, our data demonstrates that preterm labor is associated with dysregulated expression of senescence-associated genes and accumulation of senescence markers. Cellular senescence is characterized by release of pro-inflammatory mediators, including alarmins, and thus may provide a source of inflammatory signaling in a subset of patients who undergo preterm parturition

Intra‐Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116331/1/aji12443_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/116331/2/aji12443.pd

Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications.</p

Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications.</p

A Role for the Inflammasome in Spontaneous Labor at Term

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143689/1/aji12440.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143689/2/aji12440_am.pd

CXCL10 and ILâ 6: Markers of two different forms of intraâ amniotic inflammation in preterm labor

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137580/1/aji12685_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137580/2/aji12685.pd

Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

<div><p>Objective</p><p>Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.</p><p>Methods</p><p>Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.</p><p>Results</p><p>Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10^-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10^-2). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).</p><p>Conclusions</p><p>A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the <i>in vivo</i> pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.</p></div

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS

Innate lymphoid cells at the human maternalâ fetal interface in spontaneous preterm labor

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143766/1/aji12820.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143766/2/aji12820_am.pd