Th17 cells differentiated with mycelial membranes of Candida albicans prevent oral candidiasis.

Candida albicans is a human commensal that causes opportunistic infections. Th17 cells provide resistance against mucosal infection with C. albicans; however, the T cell antigens remain little known. Our final goal is to find effective T cell antigens of C. albicans that are responsible for immunotherapy against candidiasis. Here, we prepared fractions including cytosol, membrane and cell wall from yeast and mycelial cells. Proteins derived from a membrane fraction of mycelial cells effectively induced differentiation of CD4+ T cells into IL-17A-producing Th17 cells. To confirm the immunological response in vivo of proteins from mycelial membrane, we performed adoptive transfer experiments using ex vivo stimulated CD4+ T cells from IL-17A-GFP reporter mice. Mycelial membrane-differentiated CD4+ Th17 cells adoptively transferred intravenously prevented oral candidiasis by oral infection of C. albicans, compared with control anti-CD3-stimulated CD4+ T cells. This was confirmed by the clinical score and the number of neutrophils on the infected tissues. These data suggest that effective T cell antigens against candidiasis could be present in the membrane protein fraction of mycelial cells. The design of novel vaccination strategies against candidiasis will be our next step.

Antifungal activity in vitro and in vivo of a salmon protamine peptide and its derived cyclic peptide against Candida albicans.

Protamine peptide (PP) derived from salmon is a 14-mer with 10 arginine residues. We investigated the in vitro and in vivo antifungal activity of PP against Candida albicans PP showed a concentration-dependent dual mode of action, with fungicidal activity and inhibitory activity for hyphal development in vitro. At lethal concentrations of PP, intracellular accumulation of PP was energy-dependent but independent of endocytosis, and resulted in ATP efflux and the generation of reactive oxygen species in the cells. PP at sublethal concentrations inhibited hyphal development in C. albicans by binding to the cell surface. Though antifungal activity of PP was inactivated by high concentrations of NaCl, the antifungal activity of the synthetic cyclic (via a disulfide bond) form of PP (cyclic PP) was not. Cyclic PP also showed the concentration-dependent dual mode of action, and had five-fold greater antifungal activity than PP. The advantage of antifungal activity of cyclic PP compared with PP in vitro resulted in a high in vivo efficacy in a murine oral candidiasis model. Oral treatment with cyclic PP inhibited hyphal development of C. albicans on mouse tongues and protected against the development of severe candidiasis. This study shows the therapeutic potential of cyclic PP as an antifungal peptide against C. albicans.

The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation.

Natural killer (NK) cells play an important role in protective immunity against viral infection and tumor progression, but they also contribute to rejection of bone marrow grafts via contact-dependent cytotoxicity. Ligation of activating NK receptors with their ligands expressed on target cells induces receptor clustering and actin reorganization at the interface and triggers polarized movement of lytic granules to the contact site. Although activation of the small GTPase Rac has been implicated in NK cell-mediated cytotoxicity, its precise role and the upstream regulator remain elusive. Here, we show that DOCK2, an atypical guanine nucleotide exchange factor for Rac, plays a key role in NK cell-mediated cytotoxicity. We found that although DOCK2 deficiency in NK cells did not affect conjugate formation with target cells, DOCK2-deficienct NK cells failed to effectively kill leukemia cells in vitro and major histocompatibility complex class I-deficient bone marrow cells in vivo, regardless of the sorts of activating receptors. In DOCK2-deficient NK cells, NKG2D-mediated Rac activation was almost completely lost, resulting in a severe defect in the lytic synapse formation. Similar results were obtained when the Rac guanine nucleotide exchange factor activity of DOCK2 was selectively abrogated. These results indicate that DOCK2-Rac axis controls NK cell-mediated cytotoxicity through the lytic synapse formation.

Phosphatidic acid-dependent recruitment and function of the Rac activator DOCK1 during dorsal ruffle formation.

Activation of receptor tyrosine kinases leads to the formation of two different types of plasma membrane structures: peripheral ruffles and dorsal ruffles. Although the formation of both ruffle types requires activation of the small GTPase Rac, the difference in kinetics suggests that a distinct regulatory mechanism operates for their ruffle formation. DOCK1 and DOCK5 are atypical Rac activators and are both expressed in mouse embryonic fibroblasts (MEFs). We found that although PDGF-induced Rac activation and peripheral ruffle formation were coordinately regulated by DOCK1 and DOCK5 in MEFs, DOCK1 deficiency alone impaired dorsal ruffle formation in MEFs. Unlike DOCK5, DOCK1 bound to phosphatidic acid (PA) through the C-terminal polybasic amino acid cluster and was localized to dorsal ruffles. When this interaction was blocked, PDGF-induced dorsal ruffle formation was severely impaired. In addition, we show that phospholipase D, an enzyme that catalyzes PA synthesis, is required for PDGF-induced dorsal, but not peripheral, ruffle formation. These results indicate that the phospholipase D-PA axis selectively controls dorsal ruffle formation by regulating DOCK1 localization.

DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses.

To migrate efficiently through the interstitium, dendritic cells (DCs) constantly adapt their shape to the given structure of the extracellular matrix and follow the path of least resistance. It is known that this amoeboid migration of DCs requires Cdc42, yet the upstream regulators critical for localization and activation of Cdc42 remain to be determined. Mutations of DOCK8, a member of the atypical guanine nucleotide exchange factor family, causes combined immunodeficiency in humans. In the present study, we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration. By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming. Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor. This function of DOCK8 depended on the DHR-2 domain mediating Cdc42 activation. DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration. Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially.

Reversing the reversed congruency effect: directional salience overrides social significance in a spatial Stroop task.

In a spatial Stroop task, eye-gaze targets produce a reversed congruency effect (RCE) with faster responses when gaze direction and location are incongruent than congruent. On the other hand, non-social directional targets (e.g., arrows) elicit a spatial Stroop effect (SSE). The present study examined whether other social stimuli, such as head orientation, trigger the RCE. Participants judged the target direction of the head or the gaze while ignoring its location. While the gaze target replicated the RCE, the head target produced the SSE. Moreover, the head target facilitated the overall responses relative to the gaze target. These results suggest that the head, a salient directional feature, overrides the social significance. The RCE may be specific to gaze stimuli, not to social stimuli in general. The head and gaze information differentially affect our attentional mechanisms and enable us to bring about smooth social interactions.

Perceiving social gaze produces the reversed congruency effect.

Numerous studies have shown that the gaze of others produces a special attentional process, such as the eye contact effect or joint attention. This study investigated the attentional process triggered by various types of gaze stimuli (i.e., human, cat, fish, koala, and robot gaze). A total of 300 university students participated in five experiments. They performed a spatial Stroop task in which five types of gaze stimuli were presented as targets. Participants were asked to judge the direction of the target (left or right) irrespective of its location (left or right). The results showed that the social gaze targets (i.e., human and cat gaze) produced a reversed congruency effect. In contrast to the social gaze targets, the non-social gaze (i.e., fish and robot) target did not produce the reversed congruency effect (Experiments 2, 2B, 3, and 4). These results suggest that attention to the gaze of socially communicable beings (i.e., humans and cats) is responsible for the reversed congruency effect. Our findings support the notion that the theory of mind or social interaction plays an important role in producing specific attentional processes in response to gaze stimuli.

The influence of seated postures and anthropometry on lap belt fit in vehicle occupants: A 3D computed tomography study.

OBJECTIVE: In vehicle frontal collisions, it is crucial that the lap belt is designed to engage with the anterior superior iliac spine (ASIS) of occupants for a reliable restraint. This study aims to understand the influence of different seated postures on the geometrical relationship of the seat belt and the pelvis for various occupants using 3D upright and supine computed tomography (CT) systems. METHODS: The 3D shapes of bones and soft tissues around the pelvis were acquired through a CT scan for 30 participants. They were seated in a rigid seat equipped with a lap belt simulating the front seat of a small car, and wore a lap belt in three seated postures: upright, slouched and reclined. Parameters related to the likelihood of submarining occurrences, such as belt-ASIS overlap (an index for assessing the potential engagement of the lap belt with the ASIS) and the belt-pelvis angle (the difference between the belt angle and the normal direction of the anterior edge of the ilium) were compared. RESULTS: It was observed that the pelvis angle tilted rearward as the hip point was positioned forward and seatback angle increased. This can be seen in the slouched and reclined posture. The belt-pelvis angle was comparable between the slouched and the reclined postures, and was closer to zero (indicating that the lap belt path is closer to perpendicular to the anterior edge of the ilium) compared to the upright posture. In contrast, the belt-ASIS overlap increased with an increasing flesh margin of the ASIS and shallower belt angle. This suggests that the belt-pelvis angle is influenced by the seated posture whereas the belt-ASIS overlap is dependent more on an individual's anthropometry. The plot of belt-pelvis angle and belt-ASIS overlap exhibited significant variability among participants. CONCLUSIONS: The belt-pelvis angle and the belt-ASIS overlap of individuals will provide valuable information for understanding the current belt-fit location and predicting submarining occurrences for individuals in various postures when designing restraint systems.

Predictive modeling of submarining risk in car occupants based on pelvis angle and lap belt positioning.

OBJECTIVE: The engagement of the lap belt with the pelvis is critical for occupant safety during vehicle frontal crashes to prevent occupant submarining. This study aims to develop a predictive model for submarining risk based on anthropometric parameters and lap belt positioning using finite element (FE) analyses. METHODS: FE analyses were conducted using human body models representing various body shapes (a 50th percentile male, low and high BMI males, and a 5th percentile female) in three seated postures (standard, reclined, and slouched). The lap belt-ASIS overlap and the belt-pelvis angle were used as key parameters for predicting submarining risk. A logistic regression analysis was utilized to correlate submarining occurrence with the initial values of these two parameters at the beginning of impact. Subsequently, this submarining prediction model was applied to computer tomography (CT) measurements of human subjects in different seated postures (upright, reclined, and slouched), and submarining risks were calculated based on the developed model. RESULTS: FE simulations indicated that submarining was more likely to occur as the initial belt-pelvis angle approached zero and there was a smaller initial belt-ASIS overlap. The logistic regression analysis demonstrated that the initial belt-pelvis angle and belt-ASIS overlap were statistically significant for predicting submarining risk. The derived model effectively distinguished submarining occurrence based on the initial values of these two parameters. The application of the submarining model to CT measurements of human subjects showed that submarining risk was lower in the order of upright, slouched, and reclined postures. In the reclined posture, the high submarining risk was attributed to a small belt-ASIS overlap and a rearward-tilted pelvis angle; whereas in the slouched posture, the risk was mostly associated with a rearward-tilted pelvis angle. CONCLUSIONS: The submarining prediction model was developed based on the belt-pelvis angle and the belt-ASIS overlap. This predictive model may help to design restraint systems for various body types and seated postures of occupants.

Face inversion does not affect the reversed congruency effect of gaze.

In a spatial Stroop task, the eye-gaze target produces the reversed congruency effect-responses become shorter when the gaze direction and its location are incongruent than when they are congruent. The present study examined the face inversion effect on the gaze spatial Stroop task to clarify whether the holistic face processing or part-based processing of the eyes is responsible for the reversed congruency effect. In Experiment 1, participants judged the gaze direction of the upright or inverted face with a neutral expression presented either in the left or right visual field. In Experiment 2, we examined whether face inversion interacted with facial expressions (i.e., angry, happy, neutral, and sad). Face inversion disrupted holistic face processing, slowing down the overall performance relative to the performance with upright faces. However, face inversion did not affect the reversed congruency effect. These results further support the parts-based processing account and suggest that while faces are processed holistically, the reversed congruency effect, relying on the extracted local features (i.e., eyes), may be processed in a part-based manner.

Eye gaze is not unique: The reversed congruency effect on gaze and tongue targets.

In the spatial Stroop task, an arrow target produces a spatial Stroop effect, whereas a gaze target elicits a reversed congruency effect. The reversed congruency effect has been explained by the unique attentional mechanisms of eye gaze. However, recent studies have shown that not only gaze but arrow targets produced a reversed congruency effect when embedded in a complex background. The present study investigated whether non-gaze targets produce a reversed congruency effect. In Experiments 1 and 2, we used the tongue, which is not commonly used to indicate spatial directions in daily life, as a target in the spatial Stroop task, in addition to the conventional gaze and arrows. In Experiment 3, we used arrow stimuli embedded in a complex background as a target. Participants judged the left/right direction of the target presented in the left or right visual field. Although arrow and gaze targets replicated previous findings (spatial Stroop and reversed congruency effect, respectively), the tongue target produced a reversed congruency effect (Experiments 1 and 2). The spatial Stroop effect of arrow targets disappeared when they were in a complex background (Experiment 3). These results are inconsistent with previous accounts emphasising the unique status of eye gaze. We propose that temporal decay of the location code and response inhibition are responsible for the reversal of spatial interference.

Mobility gene expression differences among wild-type, Mmp20 null and Mmp20 over-expresser mice plus visualization of 3D mouse ameloblast directional movement.

Enamel forming ameloblasts move away from the dentino-enamel junction and also move relative to each other to establish enamel shape during the secretory stage of enamel development. Matrix metalloproteinase-20 (MMP20) is a tooth specific proteinase essential for proper enamel formation. We previously reported that MMP20 cleaves cadherins and may regulate ameloblast movement. Here, we used an Amelx promoter driven tdTomato reporter to label mouse ameloblasts. With these transgenic mice, we assessed ameloblast mobility group dynamics and gene expression. Three-dimensional imaging of mouse ameloblasts were observed in hemi-mandibles by using a tissue clearing technique. The three-dimensional ameloblast layer in Tg(Amelx-Mmp20) mice that overexpress MMP20 was uneven and the ameloblasts migrated away from this layer. Mouse ameloblast movement toward incisal tips was monitored by ex vivo time-lapse imaging. Gene expression related to cell migration and adhesion was analyzed in ameloblasts from wild-type mice, Mmp20-/- mice with no functional MMP20 and from Tg(Amelx-Mmp20) overexpressing mice. Gene expression was altered in Mmp20-/- and Tg(Amelx-Mmp20) mice compared to wild type. Among the genes assessed, those encoding laminins and a gap junction protein were upregulated in Mmp20-/- mice. New techniques and findings described in this study may lead to an improved understanding of ameloblast movement during enamel formation.

Dispensable Role of Aire in CD11c+ Conventional Dendritic Cells for Antigen Presentation and Shaping the Transcriptome.

Aire, the defect of which is responsible for the development of autoimmunity, is predominantly expressed in medullary thymic epithelial cells, and it controls a wide variety of genes, including those of tissue-restricted Ags, for establishing thymic tolerance. Aire is also expressed from APCs in the periphery, called extrathymic Aire-expressing cells (eTACs), and their complementing role to thymic tolerance has been suggested. eTACs are composed of two distinct classes of APCs, conventional dendritic cell (cDC)-type and group 3 innate lymphoid cell (ILC3)-like-type expressing retinoic acid receptor-related orphan receptor γt (RORγt). Although the essential role of Aire in the latter in the Th17-mediated immune response against Candida albicans has been reported, the role of Aire in the cDC-type eTACs for this action has not been examined. Furthermore, the significance of Aire in the production of the transcriptome of the cDC-type eTACs remains unknown. We have approached these issues using a high-fidelity Aire-reporter mouse strain. We found that although the cDC-type eTACs dominated ILC3-like-type eTACs in number and they served as efficient APCs for the immune response against an exogenous Ag as well as for the C. albicans-specific Th17 immune response, loss of Aire in cDC-type eTACs showed no clear effect on these functions. Furthermore, loss of Aire showed no major impact on the transcriptome from cDC-type eTACs. These results suggested that Aire in cDC-type eTACs may not have a cell-intrinsic role in the immune response in contrast to the role of Aire in ILC3-like-type eTACs.

DOCK180 is a Rac activator that regulates cardiovascular development by acting downstream of CXCR4.

RATIONALE: During embryogenesis, the CXC chemokine ligand (CXCL)12 acts on endothelial cells to control cardiac development and angiogenesis. Although biological functions of CXCL12 are exerted in part through activation of the small GTPase Rac, the pathway leading from its receptor CXC chemokine receptor (CXCR)4 to Rac activation remains to be determined. OBJECTIVE: DOCK180 (dedicator of cytokinesis), an atypical Rac activator, has been implicated in various cellular functions. Here, we examined the role of DOCK180 in cardiovascular development. METHODS AND RESULTS: DOCK180 associates with ELMO (engulfment and cell motility) through the N-terminal region containing a Src homology 3 domain. We found that targeted deletion of the Src homology 3 domain of DOCK180 in mice leads to embryonic lethality with marked reduction of DOCK180 expression at the protein level. These mutant mice, as well as DOCK180-deficient mice, exhibited multiple cardiovascular abnormalities resembling those seen in CXCR4-deficient mice. In DOCK180 knocked down endothelial cells, CXCL12-induced Rac activation was impaired, resulting in a marked reduction of cell motility. CONCLUSIONS: These results suggest that DOCK180 links CXCR4 signaling to Rac activation to control endothelial cell migration during cardiovascular development.

Pathobiont-responsive Th17 cells in gut-mouth axis provoke inflammatory oral disease and are modulated by intestinal microbiome.

Host immune response via Th17 cells against oral pathobionts is a key mediator in periodontitis development. However, where and how the Th17-type immune response is induced during the development of periodontitis is not well understood. Here, we demonstrate that gut translocation of the oral pathobiont Porphyromonas gingivalis (Pg) exacerbates oral pathobiont-induced periodontitis with enhanced Th17 cell differentiation. The oral pathobiont-responsive Th17 cells are differentiated in Peyer's patches and translocated systemically in the peripheral immune tissues. They are also capable of migrating to and accumulating in the mouth upon oral infection. Development of periodontitis via the oral pathobiont-responsive Th17 cells is regulated by the intestinal microbiome, and altering the intestinal microbiome composition with antibiotics affects the development of periodontitis. Our study highlights that pathobiont-responsive Th17 cells in the gut-mouth axis and the intestinal microbiome work together to provoke inflammatory oral diseases, including periodontitis.

CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway.

CD4(+) T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)-transgenic (tg) CD4(+) T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3Kdelta(D910A/D910A) or PI3Kgamma-deficient TCR-tg CD4(+) T cells showed similar responsiveness to CCL21 costimulation as control CD4(+) T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4(+) T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca(2+) signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis.

Neutrophils are highly motile leukocytes, and they play important roles in the innate immune response to invading pathogens. Neutrophil chemotaxis requires Rac activation, yet the Rac activators functioning downstream of chemoattractant receptors remain to be determined. We show that DOCK2, which is a mammalian homologue of Caenorhabditis elegans CED-5 and Drosophila melanogaster Myoblast City, regulates motility and polarity during neutrophil chemotaxis. Although DOCK2-deficient neutrophils moved toward the chemoattractant source, they exhibited abnormal migratory behavior with a marked reduction in translocation speed. In DOCK2-deficient neutrophils, chemoattractant-induced activation of both Rac1 and Rac2 were severely impaired, resulting in the loss of polarized accumulation of F-actin and phosphatidylinositol 3,4,5-triphosphate (PIP3) at the leading edge. On the other hand, we found that DOCK2 associates with PIP3 and translocates to the leading edge of chemotaxing neutrophils in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. These results indicate that during neutrophil chemotaxis DOCK2 regulates leading edge formation through PIP3-dependent membrane translocation and Rac activation.

Analysis of Lap Belt Fit to Human Subjects using CT Images.

In vehicle collisions, the lap belt should engage the anterior superior iliac spine (ASIS). In this study, threedimensional (3D) shapes of bones and soft tissues around the pelvis were acquired using a computed tomography (CT) scan of 10 male and 10 female participants wearing a lap belt. Standing, upright sitting, and reclined postures were scanned using an upright CT and a supine CT scan system. In the upright sitting posture, the thigh height was larger with a higher BMI while the ASIS height did not change significantly with BMI. As a result, the height of the ASIS relative to the thigh (ASIS-thigh height) became smaller as the BMI increased. Because the thigh height of females was smaller than that of males, the ASIS-thigh height was larger for females than for males. As the ASIS-thigh height was larger, the overlap of the lap belt with the ASIS increased. Thus, the lap belt overlapped more with the ASIS for the females than for the males. The abdomen outer shape is characterized by the trouser cord formed valley, the torso/thigh junction, and the anterior convexity formed between them depending on the adipose tissues. The abdomen outer shapes changed from the standing, the reclined posture to the upright sitting posture. In the reclined sitting posture, the lap belt is positioned upward and rearward relative to the ASIS, and the overlap of the lap belt with the ASIS was smaller compared to the upright posture.

SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling.

SWAP-70-like adapter of T cells (SLAT) is a novel guanine nucleotide exchange factor for Rho GTPases that is upregulated in Th2 cells, but whose physiological function is unclear. We show that SLAT(-/-) mice displayed a developmental defect at one of the earliest stages of thymocyte differentiation, the double-negative 1 (DN1) stage, leading to decreased peripheral T cell numbers. SLAT(-/-) peripheral CD4(+) T cells demonstrated impaired TCR/CD28-induced proliferation and IL-2 production, which was rescued by the addition of exogenous IL-2. Importantly, SLAT(-/-) mice were grossly impaired in their ability to mount not only Th2, but also Th1-mediated lung inflammatory responses, as evidenced by reduced airway neutrophilia and eosinophilia, respectively. Levels of Th1 and Th2 cytokine in the lungs were also markedly reduced, paralleling the reduction in pulmonary inflammation. This defect in mounting Th1/Th2 responses, which was also evident in vitro, was traced to a severe reduction in Ca(2+) mobilization from ER stores, which consequently led to defective TCR/CD28-induced translocation of nuclear factor of activated T cells 1/2 (NFATc1/2). Thus, SLAT is required for thymic DN1 cell expansion, T cell activation, and Th1 and Th2 inflammatory responses.

Bacterial-induced maternal interleukin-17A pathway promotes autistic-like behaviors in mouse offspring.

Maternal immune activation (MIA) by an infection is considered to be an important environmental factor of fetal brain development. Recent animal model on MIA induced by polyinosinic:polycytidylic acid, a mimic of viral infection, demonstrates that maternal IL-17A signaling is required for the development of autism spectrum disorder (ASD)-like behaviors of offspring. However, there is little information on bacterial infection. In this study, we aim to elucidate the influence of MIA induced by lipopolysaccharide (LPS) to mimic a bacterial infection on fetal brain development. We demonstrated that LPS-induced MIA promoted ASD-like behaviors in mouse offspring. We further found that LPS exposure induced acute phase immune response: elevation of serum IL-17A levels in MIA mothers, upregulation of Il17a mRNA expression and increase of IL-17A-producing γδ T cells in the uterus, and upregulation of Il17ra mRNA expression in the fetal brain. Blocking of IL-17A in LPS-induced MIA ameliorated ASD-like behaviors in offspring. Our data suggest that bacterial-induced maternal IL-17A pathway promotes ASD-like behaviors in offspring.