Influence of maternal inflammation on immune modulation

Adams, Rozanne Charlene McChary (2020-03)

Thesis (PhD)--Stellenbosch University, 2020.

Thesis

ENGLISH ABSTRACT: Perturbations within intrauterine microenvironment, due to maternal stressors such as chronic inflammation, metabolic dysfunction and psychological stress, can result in lifelong detrimental consequences in affected offspring. Given the substantial contribution of noncommunicable diseases to the global morbidity and mortality rate, the potential impact of maternal prenatal chronic disease on foetal development is of increasing concern. Additionally, inheritance of these developmental defects, such as behavioural, neurological, glucocorticoid and immune maladaptations, can persist for multiple generations in offspring. Although inflammation that forms part of the aetiology of chronic diseases, very few studies have reported on the immunological and glucocorticoid maladaptations in offspring exposed to maternal inflammation. Moreover, even less is known about the extent of this generational transfer, the sex-specific inheritance or the transgenerational plasticity of these maladaptations in the F1 and F2 generations. Thus, we aimed to delineate the immune functionality and glucocorticoid sensitivity in leukocytes in two generations of offspring in a mouse model of chronic induced maternal inflammation. Pregnant C57/BL/6 (F0) dams were exposed to either 10µg/kg lipopolysaccharide (LPS) or 0.9% saline (control) every seven days for the duration of gestation, with no further intervention after gestation. At 8 weeks of age, the F1 offspring were crossed with either a wild-type untreated C57/BL/6 mate or F1 LPS-affected non-sibling mate to create the second generation of offspring, F2. For experimental analyses, F0, F1 and F2 mice were profiled to assess the changes in differential splenic and circulatory leukocyte populations, corticosterone concentrations, splenic leukocyte glucocorticoid sensitivity and ex vivo cytokine responses. LPS-treated F0 dams displayed augmented glucocorticoid receptor expression in splenic leukocytes, which transferred to both F1 and F2 offspring, as well as elevated inflammatory cytokine responses in LPS-stimulated splenocytes. Both male and female F1 offspring displayed glucocorticoid hypersensitivity, indicated by elevated corticosterone and leukocyte glucocorticoid receptor levels, as well as a heightened inflammatory phenotype, which was transferred to F2. However, no sex-specific traits were observed. Interestingly, F1 LPS-affected offspring displayed sex-specific transfer of inflammatory effects to F2. The glucocorticoid dysregulation and the resultant pro-inflammatory phenotype appeared to be transferred in the F1 maternal lineage to her F2 offspring, affecting the male offspring to a greater extent. In contrast, F1 LPS males only transferred a pro-inflammatory phenotype to their offspring. The cumulative inheritance of maladaptation in F2 offspring, from F1 maternal and paternal lineages being LPS-affected, displayed blunted functional immune responses, and dampened glucocorticoid levels, but unchanged leukocyte numbers and may be suggestive of immune senescence. This study contributes to the knowledge of inheritance of susceptibility to noncommunicable chronic diseases. Our findings illustrate that parental chronic inflammation may cause lifelong reprogramming to a maladapted pro-inflammatory phenotype, persisting to at least two subsequent generations of offspring. Moreover, divergent adverse outcomes are seen in F2 offspring, in terms of sex-differences and cumulative inheritance of inflammatory effects. Given the potential impact of these findings, more focussed research in this context is required to confirm and further characterise the mechanisms underlying this paradigm, to facilitate the development of future interventions.

AFRIKAANSE OPSOMMING: Dit is bekend dat versteurings binne die mikro-omgewing in die uterus, as gevolg van moederlike stressors soos chroniese inflammasie, metaboliese disfunksie en sielkundige stres, tot nadelige gevolge vir die nageslag selfs tot in volwassenheid lei. Gegewe die aansienlike bydrae van nie-oordraagbare siektes tot wêreldwye morbiditeit en mortaliteit, is die potensiële impak van chroniese inflammasie in die moeder, op fetale programmering 'n groeiende kommer. Daarbenewens kan die oorerflikheid van hierdie ontwikkelingsdefekte, soos gedrags-, neurologiese, glukokortikoïede en immuunwanaanpassings, voortduur vir verskeie geslagte in die nageslag. Alhoewel inflammasie deel uitmaak van die etiologie van chroniese siektes, is baie min studies gerapporteer oor die immunologiese en glukokortikoïede wanaanpassings by nageslagte wat in utero aan swangerskap inflammasie blootgestel is. Daar is selfs minder bekend oor die omvang van generasie-oordrag van hierdie aspekte, sowel as die geslagspesifieke oorerwing en transgenerasie plastisiteit van hierdie wanaanpassings in die F1- en F2-generasies. In hierdie studie het ons dus ten doel gehad om die immuunfunksionaliteit en leukosiet glukokortikoïedsensitiwiteit by twee generasies nageslagte in 'n muismodel van chroniese geïnduseerde swangerskap inflammasie te omskryf. Dragtige C57/BL/6 (F0) wyfies is elke 7 dae blootgestel aan óf 10 μg/kg lipopolisakkaried (LPS) óf slegs 0,9% soutoplossing (kontrole) tot aan die einde van die swangerskap. Geen verdere ingryping is na dragtigheid gegee nie. Op die ouderdom van 8 weke is die nageslag (F1) gekruisteel met wilde-tipe onbehandelde C57/BL/6-muise of F1-LPSgeaffekteerde muise, wat nie verwant is nie, om die tweede generasie nageslag, F2, te skep. Vir eksperimentele ontledings is F0, F1 en F2 generasies omskryf om die effek van chroniese swangerskap inflammasie in differensiële milt- en bloedsomloop leukosietpopulasies, kortikosteroon, milt leukosiet glukokortikoïed sensitiwiteit en ex vivo sitokienrespons te bepaal. Die LPS-behandeling van F0-wyfies het gelei tot 'n verhoogde uitdrukking van glukokortikoïed reseptore in die meeste van die miltleukosiet-subpopulasies wat in beide F1- en F2-nageslagte ge-evalueer is, asook verhoogde inflammatoriese sitokienrespons in splenosiete wat in vitro met LPS gestimuleer is. F1-nakomelinge (beide mannetjies en wyfies) het oor die algemeen verhoogde kortikosteroonvlakke en leukosiet-glukokortikoïed reseptor-uitdrukking getoon, wat 'n aanduiding is van hipersensitiwiteit vir glukokortikoïede, sowel as 'n verhoogde inflammatoriese fenotipe wat oorgedra is na F2, ondanks die insluiting van 'n onaangetaste ouer. Hierdie fenotipe het geslagspesifieke oorerwing getoon van F1 tot F2. Glukokortikoïed wanregulering en 'n gepaardgaande proinflammatoriese fenotipe is klaarblyklik in die F1-moederlyn oorgedra na haar F2- nageslag, wat die manlike nageslag tot 'n groter mate beïnvloed het, terwyl F1 LPSmannetjies daarenteen slegs 'n meer pro-inflammatoriese fenotipe oordra, maar geen glukokortikoïed wanregulering nie. Interessant genoeg vertoon die kumulatiewe oorerwing van wanaanpassing by F2-nakomelinge, vanaf die F1-moederlike en vaderlike geslagslyne wat deur die LPS aangetas is, funksionele immuunrespons, en gedempte glukokortikoïedvlakke, maar onveranderde leukosiet getalle, wat 'n aanduiding is van immuun gerontisme. Die huidige studie dra by tot ons kennis van ouerbydrae tot die vatbaarheid vir die ontwikkeling van nie-oordraagbare chroniese siektes in nageslagte. Ons bevindinge illustreer dat chroniese ontsteking deur ouers lewenslange herprogrammering tot 'n wanaanpassende pro-inflammatoriese fenotipe in die nageslag kan veroorsaak, wat voortduur tot ten minste twee daaropvolgende generasies. Verder word uiteenlopende nadelige uitkomste in F2 generasies gesien, in terme van geslagsverskille en kumulatiewe oorerwing van inflammatoriese effekte. Gegewe die potensiële impak van hierdie bevindings, is meer gefokusde navorsing in hierdie konteks nodig om die meganismes onderliggend aan hierdie paradigma te bevestig en verder te karakteriseer, ten einde die ontwikkeling van toekomstige intervensies te vergemaklik.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/107779
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